Activation of costimulatory receptor 4-1BB enhances T helper 1 (Th1) and CD8 T cell responses in protective immunity, and prevents or attenuates several autoimmune diseases by increasing Treg numbers and suppressing Th17 or Th2 effector response. We undertook this study to elucidate the impact of enforced 4-1BB activation on the development of Sjögren's syndrome (SS)-like sialadenitis in non-obese diabetic (NOD) model of this disease. An anti-4-1BB agnostic antibody was intraperitoneally injected to female NOD mice aged 7 weeks, prior to the disease onset that occurs around 10-11 weeks of age, 3 times weekly for 2 weeks, and the mice were analyzed for SS pathologies at age 11 weeks. The salivary flow rate was markedly higher in the anti-4-1BB-treated NOD mice compared to the IgG-treated controls. Anti-4-1BB treatment significantly reduced the leukocyte infiltration of the submandibular glands (SMGs) and the levels of serum antinuclear antibodies. Flow cytometric analysis showed that the percentages of CD4 T cells, Th17 cells and plasmacytoid dendritic cells among SMG leukocytes were markedly reduced by anti-4-1BB treatment, in conjunction with a reduction in SMG IL-23p19 mRNA levels and serum IL-17 concentrations. Although the proportion of Tregs and IL-10 mRNA levels in SMGs were not altered by 4-1BB activation, IL-10 mRNA levels in salivary gland-draining lymph nodes and serum IL-10 concentrations were both markedly increased. While anti-4-1BB treatment did not affect the amount of Th1 cells and IFNγ mRNA in the SMGs, it increased these measurables in salivary gland-draining lymph nodes. Hence, agonistic activation of 4-1BB impedes the development of SS-like sialadenitis and hyposalivation.

中文翻译：

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激动剂诱导的4-1BB激活可防止非肥胖糖尿病小鼠发生Sjӧgren综合征样的涎腺炎。

共刺激受体4-1BB的激活增强了保护性免疫中的T辅助物1（Th1）和CD8 T细胞应答，并通过增加Treg数量和抑制Th17或Th2效应子应答来预防或减弱了几种自身免疫性疾病。我们进行了这项研究，以阐明在这种疾病的非肥胖糖尿病（NOD）模型中，强迫4-1BB激活对干燥综合征（SS）样涎腺炎发展的影响。向发病7周的雌性NOD小鼠腹膜内注射抗4-1BB抗体，该病发病于10-11周龄左右，每周2次，每周3次，共2周。年龄11周。与IgG处理的对照组相比，抗4-1BB处理的NOD小鼠的唾液流速明显更高。抗4-1BB处理可显着降低下颌下腺（SMG）的白细胞浸润和血清抗核抗体水平。流式细胞仪分析显示，通过抗4-1BB处理，SMG白细胞中CD4 T细胞，Th17细胞和浆细胞样树突状细胞的百分比显着降低，同时SMG IL-23p19 mRNA水平和血清IL-17浓度降低。尽管4-1BB激活并没有改变SMG中Tregs的比例和IL-10 mRNA的水平，但唾液腺引流淋巴结中IL-10 mRNA的水平和血清IL-10的浓度均显着增加。虽然抗4-1BB处理不会影响SMG中Th1细胞和IFNγmRNA的数量，但它增加了唾液腺引流淋巴结中的这些可测指标。因此，